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CD4+ T helper cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation
Gesine Hansen, … , Rosemarie H. DeKruyff, Dale T. Umetsu
Gesine Hansen, … , Rosemarie H. DeKruyff, Dale T. Umetsu
Published January 1, 2000
Citation Information: J Clin Invest. 2000;105(1):61-70. https://doi.org/10.1172/JCI7589.
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Article

CD4+ T helper cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation

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Abstract

T helper 2 (Th2) cells play a critical role in the pathogenesis of asthma, but the precise immunological mechanisms that inhibit Th2 cell function in vivo are not well understood. Using gene therapy, we demonstrated that ovalbumin-specific (OVA-specific) Th cells engineered to express latent TGF-β abolished airway hyperreactivity and airway inflammation induced by OVA-specific Th2 effector cells in SCID and BALB/c mice. These effects correlated with increased concentrations of active TGF-β in the bronchoalveolar lavage (BAL) fluid, demonstrating that latent TGF-β was activated in the inflammatory environment. In contrast, OVA-specific Th1 cells failed to inhibit airway hyperreactivity and inflammation in this system. The inhibitory effect of TGF-β–secreting Th cells was antigen-specific and was reversed by neutralization of TGF-β. Our results demonstrate that T cells secreting TGF-β in the respiratory mucosa can indeed regulate Th2-induced airway hyperreactivity and inflammation and suggest that TGF-β–producing T cells play an important regulatory role in asthma.

Authors

Gesine Hansen, Jennifer J. McIntire, V. Peter Yeung, Gerald Berry, G. Jeanette Thorbecke, Lizhen Chen, Rosemarie H. DeKruyff, Dale T. Umetsu

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(a) TGF-β–producing cells, but not Th1 cells, inhibit Th2 cell–induced a...
(a) TGF-β–producing cells, but not Th1 cells, inhibit Th2 cell–induced airway hyperreactivity in SCID mice. SCID mice received OVA-specific Th1, Th2, or TGF-β–producing cells (2.5 × 106 cells/mouse) intravenously plus intranasal OVA (50 μg) 18 hours before cell transfer. Other SCID mice received a mixture of OVA-specific Th1 and Th2 cells (2.5 × 106 cells/mouse) or a mixture of OVA-specific TGF-β–producing cells and Th2 cells (2.5 × 106 cells/mouse). To examine the specificity of the effect, some mice received KLH-specific TGF-β–producing cells and OVA-specific Th2 cells. Control mice received either OVA only (no cells transferred) or cells only without antigen (data not shown). One and 2 days after the adoptive cell transfer, OVA was again administered intranasally. Three days after adoptive cell transfer, airway hyperreactivity in response to increasing concentrations of inhaled methacholine was measured in a whole-body plethysmograph. Data are expressed as mean percent above baseline (± SEM, n ≥ 6 for each data point). Cell transfer without intranasal administration of OVA resulted in minimal airway hyperreactivity (data not shown). (b) Anti–TGF-β mAb abolishes the inhibitory effect of TGF-β–producing cells on Th2 cell–induced airway hyperreactivity. Neutralizing mAb 2G7 (500 μg/mouse) specific for active TGF-β was given intraperitoneally to SCID mice that received either a mixture of TGF-β–producing cells and Th2 cells (2.5 × 106 cells/mouse) intravenously or Th2 cells alone intravenously plus intranasal OVA on the day of cell transfer. Results are provided as mean percent above baseline (± SEM, n ≥ 5 for each data point).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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